It is well known that 11.beta.-hydroxy steroids exhibit anti-inflammatory activity. For example, hydrocortisone is an effective therapeutic agent for the treatment of rheumatoid arthritis and other inflammatory diseases. Such steroids, including cortisone, prednisolone, dexamethasone, betamethasone, prednylidene and flurandrenolone, can be produced from naturally occurring steroids by means of expensive, multistage synthesis.
An intensive research effort has been ongoing over many years to find methods for making 11.beta.-hydroxy steroids using either chemical or microbiological techniques. The most difficult step in the synthesis of such compounds is the stereospecific introduction of the hydroxyl group at the C-11 position of the steroid molecule.
U.S. Pat. No. 2,658,023 (issued Nov. 3, 1953 to Shull et al) relates to a microbiological method of preparing hydrocortisone from a starting material represented by the formula: ##STR1## The method includes incubating the starting material in the presence of any of a number of microorganisms of the genus Curvularia, e.g. Curvularia lunata, and provides hydrocortisone in up to 40% yield. It would be desirable, however, to be able to make hydrocortisone at much higher yields.
U.S. Pat. No. 3,419,470 (issued Dec. 31, 1968 to Zaffaroni et al) relates to a similar method of making various steroids, including hydrocortisone, by hydroxylating the corresponding 11-desoxy steroids (some of which have bulky groups in the 17.alpha.-position) in the presence of Curvularia lunata and up to 50% (by volume) of dimethylsulfoxide in the reaction medium. This method is reported to provide a yield of hydrocortisone of up to about 78%. It is undesirable, however, to have dimethylsulfoxide or any other organic solvent in the reaction medium in large amounts in order to avoid destruction of the microorganism. U.S. Pat. No. 3,530,038 (issued Sept. 22, 1970 to de Flines et al) relates to the preparation of hydrocortisone by hydroxylating a 11-desoxy-20-oxo compound represented by the formula: ##STR2## wherein R is an acyl of an organic carboxylic acid of 1 to 18 carbon atoms and R.sub.1 is hydrogen or the same as R, in the presence of Curvularia lunata.
A more recent reference, U.S. Pat. No. 4,353,985 (issued Oct. 12, 1982 to Petzoldt et al), relates to the preparation of hydrocortisone and related steroids by fermenting an 11-desoxy-20-oxo compound represented by the formula: ##STR3## wherein represents a single bond or a double bond; X is hydrogen, fluorine, chlorine or methyl; V is methylene; ethylene, ethylidene or vinylidene; R.sub.1 is hydrogen or C.sub.1-6 alkyl; and R.sub.2 is C.sub.1-6 alkyl, in the presence of a fungal culture of the genus Curvularia (e.g. Curvularia lunata). High yields (85-90%) of hydrocortisone or related steroids are purportedly obtained with this method.
It appears that once the method of U.S. Pat. No. 2,658,023 was known, the object of many later researchers was to improve the yield of that method by hydroxylating 11-desoxy-20-oxo compounds having more bulky or complicated groups at the 17.alpha. and/or 21-positions. However, these starting materials are often difficult and very expensive to prepare. Yet, the known method which utilizes the simpler and less expensive starting material having a hydroxy group at the 17.alpha. and 21-positions, as in the '023 patent, provides undesirably low yields of desired steroids.
It would be desirable to have a method of preparing hydrocortisone and related steriods at high yields from relatively inexpensive and readily available starting materials.